Extracellular S100A4 was reported to upregulate OPN via NF-κB pathway in osteosarcoma,34 and to maintain STAT3 phosphorylation level in neuron for functional protection of the brain.18 Coincidently, Yang XL et al. reported that S100A4 could promote STAT3 phosphorylation in HCC.15 Combined with another literature indicating that STAT3 phosphorylation might induce OPN expression in HCC,35 and with our experiment data, we proposed that S100A4rich exosomes could up-regulate OPN expression in low metastatic HCC cells via STAT3 phosphorylation. This evidence concerns the gene NFKB1 and osteosarcoma.